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THERAPEUTIC PRODUCTS GUIDANCE

GUIDANCE ON THERAPEUTIC PRODUCT

REGISTRATION IN SINGAPORE

TPB-GN-005-006

December 2020

Please visit HSA’s Guidelines on Therapeutic Product Registration webpage for the latest updates

https://www.hsa.gov.sg/therapeutic-products/guidance-documentshttps://www.hsa.gov.sg/therapeutic-products/guidance-documents

GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE DECEMBER 2020

HEALTH SCIENCES AUTHORITY – HEALTH PRODUCTS REGULATION GROUP Page 2 of 157

REVISION HISTORY

Guidance Version (Publish Date)

TPB-GN-005-006 (uploaded 31 December 2020)



TABLE OF CONTENTS

CHAPTER A GENERAL OVERVIEW ............................................................................. 11 1 FOREWORD ......................................................................................................... 11

1.1 Scope of This Guidance Document .............................................................. 11 1.2 Therapeutic Product Registration .................................................................. 13

2 APPLICANT RESPONSIBILITIES ......................................................................... 15 3 WHETHER A THERAPEUTIC PRODUCT IS SUBJECT TO PATENT ................... 15 4 PROTECTION OF CONFIDENTIAL SUPPORTING INFORMATION AND

REGISTRATION EXCLUSIVITY ............................................................................ 17 CHAPTER B REGISTRATION PROCESS ..................................................................... 18

5 PRE-SUBMISSION PREPARATION ..................................................................... 19 5.1 Product Types .............................................................................................. 19 5.2 Application Types ......................................................................................... 19 5.3 Evaluation Routes ........................................................................................ 22 5.4 Pre-Submission Consultation ........................................................................ 22

5.4.1 Pre-Submission Enquiry ................................................................... 23

5.4.2 Pre-Submission Meeting/ Notification ............................................... 23

6 APPLICATION SUBMISSION ................................................................................ 23 6.1 PRISM Application Form .............................................................................. 24 6.2 Application Dossier ....................................................................................... 24

6.2.1 Submission Requirements ............................................................... 25

6.2.2 Language and Translation................................................................ 27

6.2.3 Certifying Non-Original Documents .................................................. 29

7 APPLICATION SCREENING ................................................................................. 29 8 APPLICATION EVALUATION ................................................................................ 31

8.1 Evaluation Stages ......................................................................................... 32 9 REGULATORY DECISION .................................................................................... 33 10 POST-APPROVAL CHANGES .............................................................................. 35 11 TARGET PROCESSING TIMELINES .................................................................... 35 12 FEES ..................................................................................................................... 35

12.1 Screening Fee .............................................................................................. 35 12.2 Evaluation Fee .............................................................................................. 36

12.2.1 Changes to Application Types and Re-routing of Evaluation During

Screening ......................................................................................... 37

CHAPTER C NEW DRUG APPLICATION SUBMISSION ............................................... 39 13 APPLICATION TYPES .......................................................................................... 39 14 EVALUATION ROUTES ........................................................................................ 40

14.1 Full Evaluation Route .................................................................................... 40 14.2 Abridged Evaluation Route ........................................................................... 40

14.2.1 Priority Review ................................................................................. 41

14.3 Verification Evaluation Route ........................................................................ 42 14.3.1 NDA-3 Applications .......................................................................... 44

15 DOCUMENTARY REQUIREMENTS ..................................................................... 44 15.1 Administrative Documents ............................................................................ 45 15.2 CTD Overview and Summaries..................................................................... 60 15.3 Quality Documents ....................................................................................... 61

15.3.1 Body of Data – Drug Substance ....................................................... 61



15.3.2 Body of Data – Drug Product ........................................................... 64

15.4 Non-clinical Documents ................................................................................ 70 15.5 Clinical Documents ....................................................................................... 70 15.6 Specific Documentary Requirements for Each Evaluation Route .................. 71

15.6.1 Full Evaluation Route ....................................................................... 71

15.6.2 Abridged Evaluation Route ............................................................... 71

15.6.3 Verification Evaluation Route ........................................................... 72

CHAPTER D GENERIC DRUG APPLICATION SUBMISSION ....................................... 80 16 APPLICATION TYPES .......................................................................................... 80

16.1 Generic Product ............................................................................................ 80 16.2 Singapore Reference Product ....................................................................... 81

17 EVALUATION ROUTES ........................................................................................ 82 17.1 Abridged Evaluation Route ........................................................................... 82 17.2 Verification Evaluation Route ........................................................................ 82

18 DOCUMENTARY REQUIREMENTS ..................................................................... 84 18.1 Administrative Documents ............................................................................ 85 18.2 CTD Overview and Summaries..................................................................... 97 18.3 Quality Documents ....................................................................................... 98

18.3.1 Body of Data – Drug Substance ....................................................... 98

18.3.2 Body of Data – Drug Product ......................................................... 101

18.4 Non-clinical and Clinical Documents ........................................................... 109 18.5 Specific documentary requirements for each evaluation route .................... 110

18.5.1 Abridged Evaluation Route ............................................................. 110

18.5.2 Verification and Verification-CECA Evaluation Routes ................... 110

18.6 Documentary Requirements for Second Brand Registration of Chemical Therapeutic Products .................................................................................. 116 18.6.1 Definition ........................................................................................ 116

18.6.2 Documentary Requirements ........................................................... 116

CHAPTER E BIOSIMILAR PRODUCT APPLICATION SUBMISSION .......................... 118 19 APPLICATION TYPES ........................................................................................ 118

19.1 Biosimilar Product ....................................................................................... 119 19.2 Singapore Reference Biological Product ..................................................... 119

20 EVALUATION ROUTES ...................................................................................... 120 21 DOCUMENTARY REQUIREMENTS ................................................................... 120

21.1 Administrative Documents .......................................................................... 121 21.2 CTD Overviews and Summaries ................................................................. 121 21.3 Quality Documents ..................................................................................... 121 21.4 Non-clinical and Clinical Documents ........................................................... 122

CHAPTER F POST-APPROVAL PROCESS ................................................................ 123 22 APPLICATION TYPES ........................................................................................ 123 23 VARIATION APPLICATION PROCESS ............................................................... 125

23.1 Pre-Submission Preparation ....................................................................... 126 23.1.1 Pre-Submission Enquiry ................................................................. 126

23.1.2 Pre-Submission Meeting/ Notification ............................................. 126

23.2 Application Submission ............................................................................... 127 23.2.1 PRISM Application Form ................................................................ 127

23.2.2 Variation Application Dossier ......................................................... 127

23.3 Application Screening ................................................................................. 132 23.4 Application Evaluation and Regulatory Decision ......................................... 133



23.5 Target Processing Timelines ...................................................................... 136 23.6 Fees ........................................................................................................... 136

23.6.1 Screening Fee ................................................................................ 137

23.6.2 Evaluation Fee ............................................................................... 137

CHAPTER G MAJOR VARIATION (MAV) APPLICATION SUBMISSION ..................... 140 24 MAV-1 APPLICATIONS ....................................................................................... 140

24.1 Evaluation Routes ...................................................................................... 140 24.1.1 Full Evaluation Route ..................................................................... 141

24.1.2 Abridged Evaluation Route ............................................................. 141

24.1.3 Verification Evaluation Route ......................................................... 141

24.2 Documentary Requirements ....................................................................... 142 24.2.1 Administrative Documents.............................................................. 144

24.2.2 CTD Overviews and Summaries .................................................... 145

24.2.3 Quality Documents ......................................................................... 145

24.2.4 Non-clinical and Clinical Documents .............................................. 145

24.2.5 Specific Documentary Requirements for Each Evaluation Route ... 146

25 MAV-2 APPLICATIONS ....................................................................................... 149 25.1 Evaluation Routes ...................................................................................... 149 25.2 Eligibility Criteria ......................................................................................... 149 25.3 Documentary Requirements ....................................................................... 150 25.4 ‘Me-too’ Reclassification ............................................................................. 151

CHAPTER H MINOR VARIATION (MIV) APPLICATION SUBMISSION ....................... 152 26 APPLICATION TYPES ........................................................................................ 152 27 APPLICATION SUBMISSION .............................................................................. 153

27.1 MIV-1 applications ...................................................................................... 153 27.1.1 Submitting multiple/consequential changes .................................... 154

27.2 MIV-2 applications ...................................................................................... 154 27.2.1 MIV-2 Notification ........................................................................... 154

27.2.2 MIV-2 Do-and-Tell .......................................................................... 154



LIST OF APPENDICES

APPENDIX 1 Patent Declaration Forms

APPENDIX 2A Application Checklist (ICH CTD) for NDA and GDA

APPENDIX 2B Application Checklist (ICH CTD) for MAV

APPENDIX 3A Application Checklist (ACTD) for NDA and GDA

APPENDIX 3B Application Checklist (ACTD) for MAV

APPENDIX 4 Sample Verification Document for Translator

APPENDIX 5 Target Processing Timelines

APPENDIX 6 Guideline on Submission for Non-Prescription Therapeutic Products

APPENDIX 7 Points to Consider for Singapore Labelling

APPENDIX 8 Guideline on the Registration of Human Plasma-derived Therapeutic

Products

APPENDIX 9 Guideline on the Registration of Human Therapeutic Products

Containing Materials of Animal Origin

APPENDIX 9A Annex 1 Checklist For The Registration Of Human Therapeutic

Products Containing Materials Of Animal Origin

APPENDIX 10 Product Interchangeability and Biowaiver Request for Chemical

Generic Drug Applications

APPENDIX 11 Guideline on Drug Master File (DMF)

APPENDIX 11A Drug Master File (DMF) Submission Form

APPENDIX 11B Sample Letter of Access for DMF

APPENDIX 12 MIV Filing and Submission Enquiry Form

APPENDIX 13 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for

Chemical Therapeutic Products

APPENDIX 13A Part A: Checklist on Dossier Requirements for MIV-1 Applications for

Chemical Therapeutic Products

APPENDIX 13B Part B: Checklist on Dossier Requirements for MIV-2

(Notification)Applications for Chemical Therapeutic Products

APPENDIX 13C Part C: Checklist on Dossier Requirements for MIV-2 (Do-and-Tell)

Applications for Chemical Therapeutic Products

APPENDIX 14 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for

Biological Therapeutic Products



APPENDIX 14A Part A: Checklist on Dossier Requirements for MIV-1 Applications for

Biological Therapeutic Products

APPENDIX 14B Part B: Checklist on Dossier Requirements for MIV-2 (Notification)

Applications for Biological Therapeutic Products

APPENDIX 14C Part C: Checklist on Dossier Requirements for MIV-2 (Do-and-Tell)

Variation

APPENDIX 15 Guideline on Registration of Biosimilar Products

APPENDIX 16 Guideline on the Submission of Risk Management Plan Documents

APPENDIX 16A Singapore-Specific Annex (SSA) Template

APPENDIX 17 Guideline on PRISM Submission

APPENDIX 18 Confirmation of Quality Dossiers with Reference Agencies Approval

APPENDIX 18A Dossier Clarification Supplement



ABBREVIATIONS AND ACRONYMS

ACPM

ACRA

Advisory Committee on Prescription Medicines

Accounting and Corporate Regulatory Authority

ACTD ASEAN Common Technical Document

ACTR ASEAN Common Technical Requirements

ASEAN Association of Southeast Asian Nations

ATC Anatomical Therapeutic Chemical

BA

BCS

Bioavailability

Biopharmaceutics Classification System

BE Bioequivalence

BP British Pharmacopoeia

BSE Bovine Spongiform Encephalopathy

CECA Comprehensive Economic Cooperation Agreement

CEP Certificate of Suitability (Ph. Eur. monograph)

CHMP Committee for Medicinal Products for Human Use (formerly Committee

for Proprietary Medicinal Products) (EU)

CMC

CMI

Chemistry, Manufacturing and Controls

Consumer Medicine Information

CMS Concerned Member State

COA

COO

Certificate of Analysis

Country of Origin (Finished product manufacturer)

CPP Certificate of Pharmaceutical Product

CTD Common Technical Document

DCP Decentralised Procedure

DMF

DP

DS

Drug Master File

Drug Product

Drug Substance

EDQM

EIR

European Directorate for the Quality of Medicines

Establishment Inspection Report

EMA European Medicines Agency (EU)

FDA Food and Drug Administration (US)

FTA Free Trade Agreement

GDA Generic Drug Application



GMP

GSL

Good Manufacturing Practice

General Sale List medicine

HDPE High-Density Polyethylene

HPA Health Products Act

HPRG Health Products Regulation Group

HSA Health Sciences Authority (Singapore)

ICH International Council for Harmonisation (of Technical Requirements for

Registration of Pharmaceuticals for Human use)

INN

IPOS

International Non-proprietary Names

Intellectual Property Office of Singapore

JP

MAH

Japanese Pharmacopoeia

Marketing Authorisation Holder

MAV Major Variation

MHRA Medicines and Healthcare Products Regulatory Agency (UK)

MIV

MRP

Minor Variation

Mutual Recognition Procedure

NDA New Drug Application

OTC Over-The-Counter

P Pharmacy-Only Medicine

PD Pharmacodynamics

Ph. Eur. European Pharmacopoeia

PI Package Insert (Singapore), Product Information

PIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection

Co-operation Scheme

PIL Patient Information Leaflet

PK

PMDA

Pharmacokinetics

Pharmaceuticals and Medical Devices Agency (Japan)

PMF Plasma Master File

POM Prescription-Only Medicine

PRISM Pharmaceutical Regulatory and Information System

QOS

RMP

Quality Overall Summary

Risk Management Plan

RMS Reference Member State

SPC Summary of Product Characteristics



TGA Therapeutic Goods Administration (Australia)

TSE Transmissible Spongiform Encephalopathy

USP United States Pharmacopeia

WHO World Health Organisation



CHAPTER A GENERAL OVERVIEW

1 FOREWORD

This guidance document outlines the regulatory processes and requirements for

therapeutic product registration and should be read in conjunction with the relevant

legislation in Singapore, including:

• Health Products Act (Cap. 122D); and

• Health Product (Therapeutic Products) Regulations 2016.

The Health Products Act (HPA) provides for the legislative basis for regulating the

manufacture, import, supply, presentation and advertisement of therapeutic products,

one of the health products categories regulated under the Act.

1.1 Scope of This Guidance Document

This guidance document describes the procedures and requirements for submitting an

application to register a therapeutic product, or to make a variation application to a

registered therapeutic product.

Under the First Schedule of the HPA, a therapeutic product means any substance that:

(a) is intended for use by and in humans for a therapeutic, preventive, palliative or

diagnostic purpose, including any of the following purposes:

(i) for preventing, diagnosing, monitoring, treating, curing or alleviating any

disease, disorder, ailment, injury, handicap or abnormal physical or mental

state, or any symptom thereof;

(ii) for investigating, modifying, or replacing any physiological process;

(iii) for influencing, controlling or preventing conception; or

(iv) for inducing anaesthesia.

(b) has as its constituent any of the following active ingredients:

(i) any chemical or botanical element, naturally occurring chemical or botanical

material or chemical product obtained by chemical change or synthesis;

(ii) any metabolite from a micro-organism;



(iii) any macromolecule extracted from an organism; or

(iv) any substance derived from a biological system, including any of the following:

(A) a whole cell or micro-organism, such as a whole virus or bacterium used

as a vaccine;

(B) a part of a micro-organism, such as a sub-unit vaccine;

(C) a plasma-derived product; or

(D) a biotechnology-derived substance, such as a protein or polypeptide;

(c) exerts an inherent effect either pharmacologically, chemically or by other

physiological means, leading to its use for a therapeutic preventive, palliative or

diagnostic purpose; and

(d) is not any of the following:

(i) a medical device;

(ii) any product containing human or animal cell or tissue;

(iii) any substance administered to humans with a view to regulating, repairing,

replacing, adding or deleting a genetic sequence;

(iv) whole blood or any blood component;

(v) any Chinese proprietary medicine;

(vi) any homoeopathic medicine;

(vii) any medicated oil or balm;

(viii) any quasi-medicinal product; or

(ix) any traditional medicine.

To avoid doubt, items d(v), (vi), (vii), (viii) and (ix) have the same meaning as defined

in the Medicines Act (Cap. 176) in paragraph 2 of the Medicines (Traditional Medicines,

Homoeopathic Medicines & Other Substances) (Exemption) Order.

In making an application for a therapeutic product, applicants should ensure that the

submission requirements as specified in this guidance document are duly fulfilled. In

a situation where an applicant proposes an alternative to any of the specified

requirements, such a proposal should be accompanied by scientific justification and

discussed with HSA prior to making the submission to avoid potential rejection of the

application. Information on pre-submission consultation can be found in Chapter B;

5.4.



HSA may also request for additional information to supplement the specified

submission requirements if this is deemed necessary for the assessment of the safety,

efficacy and quality of the product for which an application is made. Information on the

submission requirements can be found in the following Chapters of this guidance.

Within this document, the term ‘quality’ is used to describe chemical, pharmaceutical

and biological data, while the term ‘non-clinical’ is used to describe preclinical,

pharmacological and toxicological data.

Applicants are advised to check HSA's website for the latest version of this guidance

document and other related therapeutic product registration guidelines.

1.2 Therapeutic Product Registration

A therapeutic product registered under the HPA is specific to the product with respect

to its:

• proprietary or brand name;

• pharmaceutical formulation;

• pharmaceutical dosage form (i.e. physical presentation) and strength; and

• indication(s) and dosing regimen.

Different formulations, dosage forms and strengths of the same chemical or biologic

entity are considered as different products and will require separate registrations for

the individual product.

Forensic Classification

Upon satisfying the regulatory requirements for quality, safety and efficacy, a

therapeutic product may be registered under one of the following forensic

classifications, which determines the level of control for access:

• Prescription-Only Medicine (POM);

• Pharmacy-Only Medicine (P); or

• General Sale List medicine (GSL).

Prescription-Only Medicines (POM) control is required in the following situations:

https://www.hsa.gov.sg/therapeutic-products/guidance-documents



(a) The product poses a direct1 or indirect2 danger to human health, even when used

correctly, if used without medical supervision;

(b) The product is frequently and widely used incorrectly and, as a result, is likely to

present a direct or indirect danger to human health;

(c) The product requires further investigation into its activity and/or side effects; and/or

(d) The product is normally prescribed by a doctor or dentist to be administered

parenterally.

The following also needs to be taken into consideration when deciding whether a

product should be classified as a POM:

(a) Whether the product contains a substance which is listed in either the Narcotic

Drug Convention or the Psychotropic Substances Convention;

(b) Whether the product is likely to lead to medicinal abuse or addiction if used

incorrectly or to be used for illegal purposes;

(c) Whether the product contains a substance which, by reason of its novelty or

properties, has the potential to fall within point (b) above;

(d) Whether the product, by reason of its pharmaceutical characteristics, is reserved

for treatments which can only be administered in a hospital;

(e) Whether the product is used in the treatment of conditions which must be

diagnosed in a hospital or in an institution with special diagnostic facilities; and/or

(f) Whether the product is intended for outpatients but may produce serious side

effects, which would require medical supervision throughout the treatment.

Pharmacy-Only Medicines (P) control is required for products that possess

characteristics which are not sufficiently critical to warrant POM control but for which

the following apply:

(a) Consultation with a pharmacist is necessary to confirm the appropriate choice of

therapy;

(b) The contraindications, drug interactions, precautions or warnings need

reinforcement by a pharmacist or are not easily recognised by the purchaser; or

(c) Special precaution is needed in the storage and handling of the product.

1 Direct danger: Adverse reactions for which there is no preventive action or which are serious, severe or of high frequency 2 Indirect danger: Masking of an underlying condition that requires medical attention e.g. cancer, heart disease



General Sale List Medicines (GSL) control is sufficient in the following situations:

(a) The product is reasonably safe and can be sold or supplied without the need for

supervision by a registered doctor, dentist or pharmacist;

(b) The contraindications, drug interactions, precautions and warnings are easily

recognised by the consumer; and

(c) The hazard to health, the risk of misuse, the risk of misdiagnosis, or the need to

take special precaution in the storage and handling the product is small.

2 APPLICANT RESPONSIBILITIES

The applicant of a product registration refers to the local company that is applying for

the product registration. The applicant company may authorise officers, permanent

employees, or designated external parties, all of whom are referred to as the “applicant

representative”, to submit the application for product registration in Singapore.

According to Section 30(10) of the HPA, an applicant, in making an application for the

registration of a therapeutic product, must ensure that all information contained in the

application is truthful and is not misleading. An applicant must inform HSA of any

emerging information that may affect the benefit-versus-risk assessment of the

therapeutic product to which the application relates, as soon as the applicant becomes

aware of such information.

The applicant is responsible for submitting the application and all the accompanying

supporting documents (including but not limited to the dossier, responses to HSA’s

queries and commitment letters).

HSA may require a statutory declaration by the applicant verifying any information

contain in or relating to the application.

3 WHETHER A THERAPEUTIC PRODUCT IS SUBJECT TO PATENT

An applicant for registration of a therapeutic product is required to make a declaration

on whether the therapeutic product for which registration is sought is subject to a



subsisting patent, pursuant to Regulation 23 of the Health Products (Therapeutic

Products) Regulations, hereafter referred to as the Regulations.

The declaration must be made in the form specified in Appendix 1 – Form 1 of this

guidance document and furnished at the time of making the application, as well as at

any other such time as HSA may require. A second declaration is required prior to the

grant of registration.

A registration application may be declared as one of the following categories:

• Category A1: where no patent is in force in respect of the therapeutic product to

which the application relates;

• Category A2: where a patent is in force in respect of the therapeutic product to

which the application relates and the applicant is either the proprietor of the patent,

or if the applicant is not the proprietor of the patent, the proprietor has consented

to or acquiesced in the grant of the registration;

• Category A3: where a patent is in force in respect of the therapeutic product to

which the application relates, the applicant is not the proprietor of the patent and

the proprietor has not consented to or acquiesced in the grant of the registration,

and the applicant is requesting for the grant of registration after the patent expires.

Such an application may not be made earlier than 18 months before the patent

expires;

• Category B: where a patent is in force in respect of the therapeutic product to which

the application relates, the applicant is not the proprietor of the patent and the

proprietor has not consented to or acquiesced in the grant of the registration, and

in the applicant’s opinion and to the best of his belief the patent is invalid or will not

be infringed by the performing of the act for which the registration is sought.

The person who is making the declaration must be duly authorised to act on behalf of

the applicant. The authorised person is ordinarily an officer of the company such as a

director, the company secretary as registered with ACRA, or equivalent. Evidence of

such authorisation of such a person by the applicant must accompany the declaration

at the point of submission. Examples of evidence of authorisation include a resolution

of board of directors, a resolution of a general meeting of the company, or an extract



of the relevant portion of the company’s articles of association. Declaration forms must

bear the original signature of the authorised person.

Where an application is declared as a Category B application, HSA will require the

applicant to serve a notice to the proprietor of the patent in the form specified in Annex

1 – Form 2 of this guidance document. An applicant may also be required to serve a

notice where HSA considers it appropriate.

The information contained in this section serves solely as guidance on the requirement

for submission of declaration on patent status for the purpose of product registration.

HSA does not provide advice on the category under which an application should be

declared or whether a therapeutic product is subject to a subsisting patent. An

applicant requiring such assistance should seek appropriate legal advice.

4 PROTECTION OF CONFIDENTIAL SUPPORTING INFORMATION AND

REGISTRATION EXCLUSIVITY

Regulation 26 and 29 of the Regulations provide for protection of confidential

supporting information relating to innovative therapeutic product applications and

exclusivity of safety and efficacy data, respectively.

Confidential information received in support of the registration of an innovative

therapeutic product is protected for a period of 5 years from the date of receipt, during

which HSA will not use the information to determine whether to grant any other

registration applications. In this regard, confidential supporting information refers to

trade secrets and information that has commercial value that would be, or is likely to

be, diminished by disclosure.

A 5-year period of exclusivity is granted for a therapeutic product for which safety and

efficacy data has been generated in support of its registration. During the exclusivity

period, a subsequent similar therapeutic product will not be able to rely on such data

generated for the earlier therapeutic product to obtain registration.



CHAPTER B REGISTRATION PROCESS

A company seeking to market a therapeutic product in Singapore must obtain

marketing approval from HSA through making an application for product

registration. The registration process involves a series of steps, as shown in Figure

1.

PRE-SUBMISSION PREPARATION

APPLICATION SUBMISSION

APPLICATION SCREENING

APPLICATION EVALUATION

REGULATORY DECISION

POST-APPROVAL CHANGES

NON-ACCEPTANCE / WITHDRAWAL

ACCEPTANCE

APPROVAL

NON-APPROVAL / WITHDRAWAL

Figure 1 Registration Process for a Therapeutic Product



5 PRE-SUBMISSION PREPARATION

The following are important considerations for an applicant to register a therapeutic

product:

(a) Knowing which type of application to apply for;

(b) Knowing which evaluation route to choose; and

(c) Arranging for a pre-submission consultation with HSA for advice, if required.

5.1 Product Types

A therapeutic product could contain either chemical or biological entity(ies) as the

active ingredient(s).

A chemical entity refers to any chemical element, naturally occurring chemical

material or chemical product obtained by chemical change or synthesis (including

macromolecules produced by chemical synthesis, such as peptides/oligo-

nucleotides), or any metabolites from a micro-organism (such as antibiotics).

A biological entity refers to any macromolecule extracted from an organism (such

as proteins, nucleic acids, proteoglycans, cytokines and growth factors), or any

substance derived from a biological system, including any of the following:

(a) A whole cell or micro-organism, such as a whole virus or bacterium used as a

vaccine;

(b) A part of a micro-organism, such as a sub-unit vaccine;

(c) A plasma-derived product; or

(d) A biotechnology-derived substance, such as a protein or polypeptide.

5.2 Application Types

In applying for a new product registration for a therapeutic product in Singapore,

there are two categories of applications – a new drug application (NDA) and a

generic drug application (GDA):




NDA-1: For the first strength of a product containing a new3 chemical or biological

entity.

NDA-2:

(a) For the first strength of a product

(i) containing a new combination of registered chemical or biological

entities;

(ii) containing registered chemical or biological entity(ies) in a new

dosage form (e.g. tablets, capsules, injectables), new presentation

(e.g. single-dose vials, multi-dose vials, pre-filled syringe, starter

packs), or new formulation (e.g. preservative-free);

(iii) containing registered chemical or biological entity(ies) for use by a

new route of administration; or,

(iv) containing registered chemical or biological entity(ies) for new

indication(s), dosage recommendation(s) and/or patient

population(s).

(b) For products that do not fall under the descriptions for NDA-1, NDA-3 or

GDA.

NDA-3:

For subsequent strength(s) of a product that has been registered or has

been submitted as an NDA-1 or NDA-2. The product name, active

ingredient, dosage form, presentation, indication, dosing regimen and

patient population should be the same as that for the NDA-1 or NDA-2.

3 i.e. not a currently registered entity in Singapore. Currently registered therapeutic products can be found in the Register of Therapeutic Products at www.hsa.gov.sg.

http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load



GDA Generic Drug Application

A generic drug application applies to a therapeutic product that contains one or more

chemical entities, and that is essentially the same as a current registered product

with respect to its qualitative and quantitative composition of active ingredients,

pharmaceutical dosage form and clinical indication.

Follow-on biologic products (also known as biosimilar products) are not eligible for a

GDA and are required to be submitted via a NDA.

GDA-1: For the first strength of a generic chemical product.

GDA-2:

For subsequent strength(s) of the generic chemical product that has been

registered or submitted as GDA-1. The product name and dosage form

should be the same as that for the GDA-1.

In cases where multiple strengths of a generic product are submitted together, the

strength of the product used in the BE study is considered as GDA-1. The remaining

strength(s) should be submitted as GDA-2.

Figure 2 is a schematic diagram illustrating the various types of applications:

Post-Approval Process, Chapter F

GDA – 2

IS PRODUCT REGISTERED?

First strength of product?

Fulfils definition of a generic product?

NDA – 1 Contains new chemical or biological entity?

NO

YES YES

NO

NDA – 2 NDA – 3

GDA – 1

NO

NO YES

YES

Figure 2 Schematic Diagram of Application Routes for Drug Registration



If there are doubts regarding which is the appropriate application type to choose,

applicants are encouraged to consult HSA via the online feedback form on the HSA

website prior to the submission of an application.

5.3 Evaluation Routes

There are four types of evaluation routes for registering a new therapeutic product:

Full route: Applies to any new product that has not been approved by

any drug regulatory agency at the time of application

submission to HSA.

Abridged route: Applies to any new or generic product that has been

evaluated and approved by at least one drug regulatory

agency.

Verification route: Applies to any new or generic product that has been

evaluated and approved by HSA’s reference drug regulatory

agencies, which are EMA4, US FDA, Health Canada, TGA

and UK MHRA5.

Verification-CECA

route:

Applies to any generic product manufactured in India which

has been evaluated and approved by HSA’s reference drug

regulatory agencies, which include EMA4, US FDA, Health

Canada, TGA and UK MHRA5.

Applicants should refer to Chapters C, D and E for detailed information about the

selection of appropriate evaluation routes for NDA, GDA and Biosimilar product

applications, respectively.

5.4 Pre-Submission Consultation

Applicants are encouraged to contact HSA prior to the submission of an application

if questions arise or clarification is required.

4 For products approved via the Centralised Procedure 5 For products approved via the national procedure or where MHRA acted as the RMS for the MRP or Decentralised Procedures in Europe

https://crm.hsa.gov.sg/event/feedback



Advice given at pre-submission consultations will be based on information current

at the time of the consultation and have no bearing on the eventual outcome of the

application concerned.

5.4.1 Pre-Submission Enquiry

An applicant may submit a Pre-Submission Enquiry via the online feedback form

on the HSA website to clarify any matters concerning the application prior to

submission.

5.4.2 Pre-Submission Meeting/ Notification

An applicant may request for a pre-submission meeting if a face-to-face

consultation with HSA is necessary to address specific submission issues. The

request can be made via the online feedback form on the HSA website.

The request should state the purpose, agenda and proposed date and time for the

meeting and be made at least 3 weeks prior to the meeting date, and relevant

meeting documents (e.g. presentation slides, briefing documents, etc.) should be

provided at least 1 week before the meeting.

A pre-submission meeting is not compulsory for an application filed via the full

evaluation route. Nonetheless, the applicant is required to notify HSA at least two

months prior to the intended submission date. The notification should include

information on the product name (if available), active ingredient(s), summaries of

the quality, non-clinical and clinical data (e.g. Overviews), planned submissions in

other countries, and planned date of submission to HSA.

6 APPLICATION SUBMISSION

The submission of an application comprises two key steps – (i) online submission

of the application form via PRISM and (ii) submission of the technical dossier.

https://crm.hsa.gov.sg/event/feedbackhttps://crm.hsa.gov.sg/event/feedbackhttps://www.hsa.gov.sg/e-services/prism



6.1 PRISM Application Form

All applications must be made online via PRISM. Please refer to Appendix 17

Guideline on PRISM submission for further details.

6.2 Application Dossier

The technical dossier accompanying the application should be submitted within 2

working days of the PRISM application submission to prevent delays in the

processing of the application. The date of receipt of the actual technical dossier

by HSA will be taken as the submission date where the processing time starts.

Application dossiers should be organised in a CTD format. The CTD provides a

common format for the preparation of a well-structured submission dossier. It uses

a modular framework described in ICH Topic M4 or the ASEAN guidelines on the

Common Technical Document for Registration of Pharmaceuticals for Human use:

Organisation of the Dossier. This guidance document should be read in conjunction

with the current version of the ICH CTD and the ASEAN CTD (ACTD) guidance

documents.

Either the ICH CTD or the ACTD format is acceptable for making a submission to

HSA. Table 1 summarises the organisation of the respective format:

http://www.ich.org/https://www.hsa.gov.sg/therapeutic-products/guidance-documents



Table 1 Format of the ICH CTD and ACTD

Documents Location in

ICH CTD ACTD

Administrative Documents and

Product Information

Module 1 Part I

Common Technical Document

Overview and Summaries

Module 2 Incorporated in

Parts II, III and IV

Quality documents Module 3 Part II

Non-clinical documents Module 4 Part III

Clinical documents Module 5 Part IV

Application checklists for both ICH CTD and ACTD dossiers are provided in

Appendix 2A and 3A, respectively, to guide applicants on the submission

requirements and to ensure completeness of the dossier. Each application must

be accompanied by a checklist duly completed by the applicant and attached

in PRISM.

Applicants should note that the CTD format cannot be changed once the

application is submitted. Any subsequent variation applications for the product

should follow the same format.

6.2.1 Submission Requirements

The complete application dossier – i.e. Modules 1 to 5 of the ICH CTD or Parts I to

IV of the ACTD – must be submitted in an electronic format.

All documents required under Module 1/Part I must be submitted in softcopy in

PRISM. Colour scanned copy of the original documents should be submitted and

original hardcopy of documents are not required. However, HSA reserves the rights

to request for the submission of the original or certified true copy of the submitted

document if there is any doubt that the submitted scanned document is not an

accurate reflection of the original document.



Please refer to section 6.2.3 for more information on certifying non-original

documents if the original documents cannot be provided.

For Modules 2 to 5/Parts II to IV, applicants can opt to attach the documents either

in full into PRISM section 7 (Supporting Attachments) or submit the softcopies (e.g.

PDF format) in a CD/DVD.

Submitting a CD or DVD

When submitting a CD/DVD, applicants are encouraged to organise the dossier (i.e.

folders and subfolders) according to the CTD format and to include bookmarks in

all documents to facilitate the retrieval of documents.

Files containing the below scripts will not be accepted due to cybersecurity reasons:

The CD/DVD should be properly labelled with the following information:

• PRISM application number;

• PRISM submission date;

• Product name;

• Application type; and

• Contents of the CD/DVD (e.g. Module 2, 3 and 5).

Applicants must ensure the access to the content of CD/DVD. For protected files,

password(s) must be provided as appropriate.



Upon acceptance of the application for evaluation, applicants will be notified if

additional copies of clinical documents (in CD/DVD) will be required.

6.2.2 Language and Translation

All documents submitted in support of an application to HSA must be in English.

For documents in their original language which is not English, a certified translation

or a verified translation may be acceptable.

Translation

type

Type of

Documents

Requirements

Certified

Translation

▪ Official

certificates

issued by

the drug

regulatory

agency of a

country

▪ Proof of

approval

issued by

the drug

regulatory

agency of a

country

Notarisation & Authentication

(a) Notarisation

▪ These documents must be notarised by a

notary public in country where document is

issued.

▪ Details of particulars to be included by

notary:

(i) The name of the notary;

(ii) A statement that the notary is duly

admitted to practice in the place of issue

of the certificate;

(iii) The names of the signatories and the

capacity in which they have executed the

document, whether on their own behalf or

in an official or representative capacity;

(iv) A statement authenticating the

signatures of the parties and, where

appropriate, indicating that evidence has

been produced to the notary proving the

capacity in which they have executed the

document;

(v) The place and date of issue of the

notarial certificate; and



(vi) The signature and seal of the notary.

(b) Authentication

▪ These documents must be authenticated

(i.e. the origin of the document is attested

to) by one of the following government

bodies:-

(i) The Ministry of Foreign Affairs of the

country in which the document was

issued; or

(ii) The Singapore Embassy/Consulate in

the country where the document was

issued.

Applicants are advised to consult the Singapore

Embassy/Consulate in the country where the

document originated regarding the local

requirements for document legalisation, as

these may deviate from the process as outlined

in the preceding paragraph.

Verified

Translation

▪ Technical

documents

(e.g.

package

insert,

submission

dataset)

Verification Document

▪ A verification document must be provided

by the translator of the document into the

English language.

▪ The verification document must state that

the translation into English is accurate.

▪ Details of particulars to be included in

verification document:

(i) the name of translator;

(ii) a statement that he/she is well versed in

English and the relevant foreign

language; and

(iii) a reference to the document being

translated.



Refer to the sample verification document for

translator enclosed in Appendix 4.

6.2.3 Certifying Non-Original Documents

If the softcopy official document (e.g. CPP, GMP certificate) submitted to HSA in

PRISM is not a scan of the original document, the document must be certified prior

to submission. A certified true copy certifies that the photocopy presented is a true

and accurate copy of the original document. Acceptable certification of documents

to support therapeutic product applications to HSA can be done by the Company

Director or Company Secretary as registered with ACRA or above, or by an

independent authority such as a lawyer, notary public, Commissioner for

Oaths/Declarations/Affidavits, Justice of Peace, the original issuer of the document

or Embassy/Consulate. A notarised and authenticated copy is the same as a

certified true copy.

A certified true copy of an approval letter requires certification by the drug regulatory

agency that issued the approval letter, a notary public or the Singapore

Embassy/Consulate in the country where the approval letter was issued.

Certification of an approval letter is not required if the approval letter is available on

the drug regulatory agency’s website. In this instance, applicants can provide the

internet address (URL) for validation by HSA.

7 APPLICATION SCREENING

Following a submission made via PRISM and the receipt of the application dossier

by HSA, the application will be screened to ensure the correctness of the application

type and the completeness of the dossier. The date of receipt of the application

dossier (i.e. the technical dossier [e.g. in a CD/DVD] including the application

checklist) will be taken as the submission date and the start of the screening

timeline.

During screening, if an application is identified to be more appropriately submitted

under a different application type, the applicant will be informed of this change and



the necessary actions to effect this change via an Input Request. More information

on the change in application type is described in section 12.2.1 Changes to

Application Types and Re-routing of Evaluation During Screening.

For applications with the following major deficiencies, the applicant will be

requested to withdraw the application, as screening cannot proceed without the

dossier:

• entire dossier sections not submitted (drug substance, drug product, clinical);

• Drug Master File (DMF) not submitted (where applicable); or

• assessment reports not submitted (for verification route).

Applicants should ensure that the dossier is compiled according to the required

format. Failure to adhere to the required CTD format will lead to the non-acceptance

of the dossier without screening.

If deficiencies are identified in an application dossier, a screening query stating the

deficiencies will be issued via Input Request to the applicant. The stop-clock starts

when an Input Request is sent and ends upon receipt of a complete and satisfactory

response to the query. The total number of Input Requests sent during screening is

capped at two. Applicants will be given 20 working days to respond to each Input

Request, starting from the date the Input Request is sent.

The application will only be accepted when all deficiencies have been adequately

addressed and HSA is satisfied that the dossier is complete for evaluation. An

acceptance notice will then be issued via PRISM and the date of acceptance of the

application will be taken as the start of the evaluation timeline. For full and abridged

applications, applicants will be required to submit additional copies of the dossier in

CD/DVD format after acceptance.

If the applicant fails to address the deficiencies raised during screening, the

application will not be accepted for evaluation. An Input Request will be issued to

the applicant to withdraw the application. If the application is subsequently re-

submitted, it will be processed as a new application.



8 APPLICATION EVALUATION

Once the application is accepted, the evaluation stage begins. Evaluation queries

may be issued via Input Request to the applicant if clarification or additional

information is required.

The stop-clock starts whenever HSA issues a query and ends upon the receipt of a

complete and satisfactory response from the applicant.

In situations where the applicant is unable to provide a complete response within

the specified timeframe, the applicant should notify HSA as soon as possible after

receiving HSA’s queries. The application will be considered withdrawn if the

applicant fails to observe the specified response deadline.

Applicants are reminded that the submission of additional supporting data not

requested by HSA following the acceptance of the application will not be

considered, unless prior arrangement with HSA is made for the submission

concerned. During the evaluation process, HSA may assess that the application is

more suitably evaluated via an alternative route, in which case the application will

be re-routed to the appropriate route. Any re-routing of the application will be

discussed with the applicant.

HSA may engage external evaluators, experts and advisory committees in the

evaluation process, when necessary. These experts include scientists and

clinicians from both local and overseas institutions. All external evaluators and

experts are bound by agreement to protect the information made available to them.

The identity of the external evaluators is kept confidential.

NOTE: The screening process only checks for the completeness of the application dossier for evaluation. The acceptance of the dossier for evaluation does not denote the adequacy of the data for regulatory approval.



8.1 Evaluation Stages

The progress status of the evaluation is available for certain application types and

evaluation routes. Table 2 describes the applicable product applications and the

stages of the evaluation:

Table 2 Product Applications Applicable for Notification of Stages During

Evaluation

Stages of

Notification to

Applicant

1st Stage 2nd Stage 3rd Stage 4th Stage

Application

Type

Evaluation

Route

Evaluation Status

Acceptance

for

Evaluation

Active

Evaluation

in Progress

Evaluation at

Midway

Completed

Evaluation

NDA-1

NDA-2

NDA-3

Full or

Abridged

Application

is accepted

for

evaluation.

This marks

the start of

the

evaluation

timeline.

When active

evaluation

is in

progress for

the

application

Application is

approximately

midway

through the

evaluation

(provided that

there were no

prior stop-

clocks which

may affect the

evaluation

progress).

Applicants can

expect to

receive the

first set of

queries from

HSA during

this stage.

Evaluation is

completed for

the application.

Application is

now

undergoing the

regulatory

decision phase,

after which a

regulatory

decision# will

be issued.

Applicants can

still expect

further queries

from HSA

during this

stage.

GDA-1

GDA-2

Abridged,

Verification,

or

Verification-

CECA



#The issuance of a regulatory decision marks the end of the evaluation timeline for a product

application.

Applicants may view the evaluation stage via Track@PRISM. The following

screenshots illustrate the change in stages of a pending application:

Applicants are also notified via system-generated emails whenever an evaluation

stage change occurs.

9 REGULATORY DECISION

A regulatory decision is made following the conclusion of the benefit-risk

assessment by HSA based on the data submitted in support of the application.

Applicants will be notified of one of the following outcomes:

Enter PRISM application to view stage of evaluation.

Choose these options from the drop-down lists.

Active Evaluation

The evaluation stage is seen here.

https://www.hsa.gov.sg/e-services/prism



• Approval – the application satisfies the registration requirements for quality,

safety and efficacy;

• Approvable – when the application can be approved subject to adequate

response to minor deficiencies;

• Non-approvable – when the application has major deficiencies; or

• Rejection – when the response provided by the applicant fails to address the

major deficiencies specified in HSA’s non-approvable decision.

‘Approval’ and ‘rejection’ are final decisions issued by HSA.

For an ‘approvable’ application, the applicant will be informed of the conditions for

approval and is required to fulfil these conditions within a stipulated timeframe prior

to the grant of a final approval.

For a ‘non-approvable’ application, the applicant will be informed of the deficiencies

leading to the non-approvable decision. If the applicant wishes to address the

specified deficiencies, the response should be based on the original data set

submitted to HSA and furnished within the stipulated timeframe. New data not

previously reviewed by HSA during the evaluation of the application concerned will

not be accepted.

An application will be considered withdrawn if the applicant fails to reply within the

stipulated timeframe subsequent to an ‘approvable’ or a ‘non-approvable’ decision.

Once the application is withdrawn, it is considered closed and the applicant will be

required to make a new application if he wishes to pursue the regulatory approval

for the product concerned.

Upon an ‘approval’ regulatory decision, the product will be added to the Register of

Therapeutic Products.

HSA may register the product subject to post-approval commitments. In such

circumstances, the applicant will be required to furnish a letter of commitment

stating the undertakings concerned.

http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=loadhttp://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load



Applicants must take note of the registration conditions and the post-approval

commitments specified in the registration. The registration conditions can be viewed

at Enquire@PRISM.

10 POST-APPROVAL CHANGES

Upon the registration of a product, product registrants are responsible for ensuring

the product’s quality, efficacy and safety through its life cycle.

HSA must be notified of any changes to the product’s quality, efficacy and safety

as per Chapter F of this guidance.

11 TARGET PROCESSING TIMELINES

Please refer to Appendix 5 for information on target processing timelines for the

different application types and evaluation routes.

12 FEES

As the fees may be subject to revision from time to time, applicants are advised to

visit the HSA website for updated information on fees .

Payment can be made via GIRO or other electronic payment modes such as eNets

or eCredit card.

12.1 Screening Fee

A screening fee is payable at the time of online submission via PRISM and is non-

refundable once the application is submitted via PRISM.

For payment via GIRO, the screening fee will be debited upon the successful

submission of an online application.

NOTE: Applicants are strongly encouraged to apply for a GIRO account (click here for GIRO application form) with HSA to facilitate payments for future submissions and subsequent payment for retention fee for the registered products.

http://eservice.hsa.gov.sg/osc/portal/jsp/AA/process.jsp?eService=ENQhttps://www.hsa.gov.sg/therapeutic-products/feeshttps://www.hsa.gov.sg/docs/default-source/e-services/form-for-inter-bank-giro-application.pdfhttps://www.hsa.gov.sg/docs/default-source/e-services/form-for-inter-bank-giro-application.pdf



For payment via other electronic payment modes (i.e. eNETs or eCredit card), the

screening fee must be paid before the application is considered successfully

submitted online.

12.2 Evaluation Fee

An evaluation fee is payable upon the acceptance of the dossier for evaluation and

is non-refundable once the application is accepted.

For payments via GIRO, the evaluation fee will be debited upon the acceptance of

the application.

For payments via other electronic payment modes (i.e. eNETs or eCredit card), the

evaluation fee will be collected together with the screening fee. In the event that the

application is not accepted for evaluation, the fee collected will be refunded to the

applicant’s bank account.

Applicants may opt for the progressive payment scheme. This is an opt-in scheme

eligible for applicants who make payment via GIRO and is only applicable to the

application types listed in Table 3:

Table 3 Product Applications Applicable for Progressive Payment Scheme

Percentage of Evaluation Fee Payable at Each Stage

Application

Type

Evaluation

Route

Evaluation Status

Acceptance for

Evaluation

Active Evaluation

in Progress

Evaluation

at Midway

Completed

Evaluation

NDA-1

NDA-2

NDA-3

Full or

Abridged

30% 40% 20% 10%

GDA-1

GDA-2

Abridged,

Verification

or

Verification

-CECA



Once the application is submitted, the selected payment scheme (full or

progressive) cannot be amended. Applicants who wish to change their selected

payment scheme will have to withdraw and re-submit the application(s); and any

upfront payment made (e.g. screening fee) is non-refundable.

For applications under the progressive payment scheme, in the event that the

application is withdrawn during the evaluation stage, any fees that had been

charged, but not debited from the GIRO account would remain payable. Any paid

fee is non-refundable.

12.2.1 Changes to Application Types and Re-routing of Evaluation During

Screening

If an application type or evaluation route is incorrectly selected, applicants will be

informed via an Input Request. Such changes may result in a different evaluation

fee upon acceptance of the application.

In the situation where the applicant decides not to pursue the application due to the

changes, the screening fee is not refundable.

For applications which require withdrawal and resubmission, the screening fee is

not refundable. Applicants may wish to seek clarification on the appropriate

application type or evaluation route via the online feedback form on the HSA

website prior to the submission.

12.2.1.1 Change of Sub-Type within the Same Application Type

This refers to a change in the sub-type of the selected application type (e.g. from

NDA-1 to NDA-2, NDA-2 to NDA-3, or GDA-1 to GDA-2).

The applicant will be informed of the change via an Input Request. However,

applicants should not amend the application type field in the PRISM application

form. The change will be effected by HSA at the point of acceptance of the

application.




In the situation where the applicant decides not to pursue the application due to the

said change, the applicant must withdraw the application prior to acceptance to

avoid the evaluation fee being charged.

12.2.1.2 Change of Application between Different Application Types

This refers to a change in the application type between GDA to NDA or vice versa.

The applicant will be required to withdraw and resubmit the application if the

applicant intends to pursue the application.

12.2.1.3 Change of Evaluation Route

This refers to a change in evaluation route (e.g. Full to Abridged, Verification to

Abridged, Abridged to Verification, etc.).

The applicant will be required to withdraw and resubmit the application if the

applicant intends to pursue the application.



CHAPTER C NEW DRUG APPLICATION SUBMISSION

This chapter applies to new drug applications for products containing new chemical

and biological entities. Applicants are advised to refer to Chapter E for new drug

applications for biosimilar products.

13 APPLICATION TYPES


NDA-1: For the first strength of a product containing a new6 chemical or biological

entity.

NDA-2:

(a) For the first strength of a product

(i) containing a new combination of registered chemical or biological

entities;

(ii) containing registered chemical or biological entity(ies) in a new

dosage form (e.g. tablets, capsules, injectables), new presentation

(e.g. single-dose vials, multi-dose vials, pre-filled syringe, starter

packs), or new formulation (e.g. preservative-free);

(iii) containing registered chemical or biological entity(ies) for use by a

new route of administration; or

(iv) containing registered chemical or biological entity(ies) for new

indication(s), dosage recommendation(s) and/or patient

population(s).

(b) For products that do not fall under the descriptions for NDA-1, NDA-3 or

GDA.

NDA-3:

For subsequent strength(s) of a product that has been registered or has

been submitted as an NDA-1 or NDA-2. The product name, active

ingredient, dosage form, presentation, indication, dosing regimen and

patient population should be the same as that for the NDA-1 or NDA-2.

6 i.e. not a currently registered entity in Singapore.



14 EVALUATION ROUTES

There are three evaluation routes for an NDA – full, abridged and verification

evaluation routes. The eligibility criteria are different for each evaluation route.

Applicants should be familiar with the criteria for each evaluation route because

each route has different documentary requirements.

Figure 3 is a schematic diagram illustrating the evaluation routes for NDAs:

14.1 Full Evaluation Route

Full evaluation applies to a product that has not been approved by any drug

regulatory agency at the time of submission.

For a submission under the full evaluation route, the applicant is required to notify

HSA via the online feedback form on the HSA website at least two months prior to

the intended submission date of the application dossier. The notification should

include information on the product name (if available), active ingredient(s),

summaries of the quality, non-clinical and clinical data (e.g. Module 2.4 Non-clinical

Overview, Module 2.5 Clinical Overview), planned submissions in other countries,

and the planned date of submission to HSA.

14.2 Abridged Evaluation Route

Abridged evaluation applies to a product that has been approved by at least one

drug regulatory agency at the time of submission.

Approved by HSA’s reference agencies and meets verification criteria?

Is the product registered with any drug regulatory agency?

NO

FULL ROUTE

ABRIDGED ROUTE

YES

NO

YES

VERIFICATION ROUTE

NDA

Figure 3 Schematic Diagram of Evaluation Routes for NDAs




14.2.1 Priority Review

For NDAs submitted via the abridged evaluation route, the applicant may request

for priority review for a life-saving drug if there are unmet medical needs. The

following are the criteria that will be considered for granting a priority review:

(a) The drug is intended for the treatment of a serious life-threatening condition and

demonstrates the potential to address local unmet medical needs, as defined

by:

(i) the absence of a treatment option; or

(ii) the lack of safe and effective alternative treatments, such that the drug would

be a significant improvement compared to available marketed products, as

demonstrated by

(A) evidence of increased effectiveness in treatment, prevention, or

diagnosis;

or

(B) elimination or a substantial reduction of a treatment-limiting drug

reaction.

(b) Disease conditions that are of local public health concern will be given primary

consideration for priority review. Currently these include:

(i) cancer; and

(ii) infectious diseases: dengue, tuberculosis, hepatitis and malaria.

The request for priority review should be made at the point of the application

submission and accompanied by justifications (attached in PRISM; see section 15.1

– Introduction (CTD/PRISM section 1.3)) for requesting for a priority review and how

the product is expected to benefit patients, as substantiated by the following

evidence:

• The seriousness of the disease condition, local and worldwide mortality rates,

anticipated morbidity and debilitation as a consequence of the disease;

• Local epidemiology data and volume of requests through the exemption route

on a named-patient basis;

• The unmet needs, current available treatment options and standard therapies,

and the inadequacy of current therapies;



• The extent to which the product is expected to have a major impact on medical

practice, its major benefit, and how it addresses the unmet needs; and

• Clinical evidence supporting the claims of significant improvement compared to

available treatments.

HSA reserves the right to deny a request for priority review if it is deemed

appropriate. The decision for the granting of priority review would be conveyed to

the applicant at the point of acceptance of the application for evaluation.

14.3 Verification Evaluation Route

Therapeutic products with similar indication(s), dosing regimen(s), patient group(s),

and/or direction(s) for use that have been approved by at least two of HSA’s

reference drug regulatory agencies may be submitted via the verification evaluation

route. HSA’s reference drug regulatory agencies are:

• Australia Therapeutic Goods Administration (TGA);

• Health Canada (HC);

• US Food and Drug Administration (FDA);

• European Medicines Agency (EMA) via the Centralised Procedure; and

• UK Medicines and Healthcare Products Regulatory Agency (UK MHRA) via

- the national procedure, or

- as the Reference Member State (RMS) via the Mutual Recognition

Procedure or Decentralised Procedure.

However, approval by these reference drug regulatory agencies does not oblige

HSA to approve the application. HSA may also re-categorise applications to other

evaluation routes if the applications did not meet the eligibility criteria and/or

submission requirements.

One of the reference drug regulatory agencies must be declared as the primary

reference agency. The chosen primary reference agency is defined as the

reference drug regulatory agency from which the qualifying supporting documents

(as outlined in this guidance) will be submitted.



Additional eligibility criteria for the verification route include:

• The application must be submitted to HSA within three years from the date of

approval by the chosen primary reference agency;

• A declaration letter issued by the product owner/applicant must be provided

stating that all aspects of the drug product’s quality, including but not limited to

the formulation, manufacturing site(s), release and shelf life specifications and

primary packaging, are identical to that currently approved by the chosen

primary reference agency at the time of submission. However, a different

container closure system type (e.g. Alu/Alu blister vs. HDPE bottle) may be

proposed to meet ASEAN stability requirements;

• If a Drug Master File is submitted, then a separate declaration letter issued by

the applicant must also be provided to state that the DMF submitted to HSA is

identical to that submitted to the chosen primary reference agency;

• The product does not need a more stringent assessment as a result of

differences in local disease patterns and/or medical practices (e.g. some anti-

infectives);

• The product and its intended use – i.e. indication(s), dosing regimen(s) and

patient group(s) – have not been rejected, withdrawn, or approved via appeal

process or are not pending deferral by a drug regulatory agency for safety and/or

efficacy reasons; and

• The product is not a biological product.

The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s)

for use should be the most stringent among those approved by the reference drug

regulatory agencies. In the event that the chosen primary reference agency does

not bear the most stringent indication(s), dosing regimen(s), patient group(s) and/or

direction(s) of use, the clinical assessment report from the reference drug regulatory

agency that does meet these requirements should be submitted. Reports from the

public domain are acceptable. The proposed PI/PIL should be identical to that

bearing the most stringent indication(s), dosing regimen(s), patient group(s) and/or

direction(s) of use (with the exception of country-specific information).

For a product with a proposed indication that has been designated as an Orphan

Drug by at least one reference drug regulatory agency or a product that has been



approved by at least one reference drug regulatory agency via an accelerated/fast-

track approval, approval under exceptional circumstances or equivalent approval

process, the applicant should consult HSA on the eligibility of such a product

through the verification route prior to its submission.

14.3.1 NDA-3 Applications

For the NDA-3 application type, the verification evaluation route may be applied to

the registration of subsequent strengths of a currently-registered product in

Singapore. To qualify for the verification evaluation route for an NDA-3 application:

• if the product has been evaluated and approved by at least one of HSA’s

reference drug regulatory agencies, then the NDA-3 must be submitted within

two years from the date of approval by that reference drug regulatory agency;

or

• if the product has been evaluated and approved by at least two of HSA’s

reference drug regulatory agencies, then the NDA-3 must be submitted within

three years from the date of approval by the chosen primary reference agency.

All other eligibility criteria for the verification evaluation route as stated in section

14.3 above will apply to NDA-3 applications except for the following:

• The proposed indication(s), dosing regimen(s), patient group(s), and/or

direction(s) for use must be identical to the corresponding approved NDA-1

and/or NDA-2 product(s); and

• The proposed PI/PIL should also be consistent with that currently approved for

the corresponding NDA-1 and/or NDA-2 product(s).

15 DOCUMENTARY REQUIREMENTS

Table 4 outlines the CTD Modules/Parts required for NDAs submitted under each

evaluation route:

Table 4 Dossier Submission Requirements for NDAs

Documents Location in Module/Part required for



ICH

CTD

ACTD Full

NDA

Abridged NDA Verification NDA

Administrative

Documents

Module

1

Part I Yes Yes Yes

Common

Technical

Document

Overview and

Summaries

Module

2

Incorporate

d in Parts

II, III and

IV

Yes Yes Yes

Quality

docume